Coronary heart disease (CHD) remains the leading cause of death and disability in our society. Every year, approximately 500,000 deaths in the U.S. and 7.2 million globally are caused by this disease. As many women die from CHD as do men. The opportunity to reduce the major causes of CHD is at hand. By focusing on prevention, we can have a major impact on people's health. However, major gaps exist in our knowledge about nutritional adequacy, nutrient-disease interactions, and effective strategies to implement the current recommendations, which have the widely recognized potential to decrease the burden of the American population. Moreover, we know little about specific genes and genetic variations that affect risk directly and indirectly by the way they interact with nutrients. Therefore, one of the goals specified by U.S. Health Organizations is to characterize the numerous genes that likely play a critical role in the causation of major diseases or the protection of individuals from such diseases and to investigate their interactions with nutrients. Similarly, the roles of specific polymorphic forms of genes that influence individual susceptibility to specific dietary factors must be identified. Hence, the primary aims of this proposal are: 1. To evaluate whether polymorphisms at the proposed candidate genes [Peroxisome Proliferator-Activated Receptors (PPARA and PPARG), Estrogen Receptor (ESRA), Sterol Regulatory Element-Binding Proteins (SREBP1 and SREBP2), SREBP cleavage-activating protein (SCAP), 3- Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), Scavenger Receptor Class B-I (SRBI), Intestinal Fatty Acid-Binding Protein (FABP2), and ATP-Binding Cassette 1 (ABC1)] are associated with plasma lipid variability and CHD in a free-living population, and 2. To examine interactions between those gene variants and dietary factors. Information about such gene-diet interactions will provide significant clues about the mechanisms by which dietary factors regulate lipid metabolism. The candidate genes proposed contribute to variation in plasma low-density lipoprotein cholesterol (LDL,C), high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels. The study population consists of subjects participating in the Framingham Offspring (FOS) and OMNI (Minorities) studies (n approximately 3,180). The primary outcomes are LDL-C, HDL-C, TG, remnant-like particle-C levels, lipoprotein particle size, and measures of LDL oxidation. Secondary outcomes are carbohydrate metabolism- related measures (i.e., glucose and insulin levels). Our main hypothesis is that genetic variants at these loci are associated with variability of plasma lipid measures, thus determining CHD risk. These effects are modulated by dietary and behavioral factors. This knowledge will facilitate the generation of genetic screening panels that will assist in individual assessment of CHD risk and dietary therapeutic counseling.